Molecule of the Month

Simian Virus 40

Simian virus 40 is an example of how simple a virus can be and still perform its deadly job. Viruses are tiny machines with a single purpose: to reproduce themselves. They enter cells and hijack their synthetic machinery, forcing them to create new viruses. SV40 does this with very little molecular machinery. It is enclosed by a spherical capsid composed of 360 copies of one protein, seen in PDB entry 1sva , and a few copies of two others. This capsid is just big enough to enclose a small circle of DNA 5243 nucleotides long, which contains the barest minimum of information needed to get into the cell and make new viruses.

DNA Circles

The circular SV40 genome is found in the cell as a "mini-chromosome" wound into a handful of nucleosomes, as shown here. It only has enough space to encode a few functions, since it all has to fit inside the tiny capsid. It has a regulatory region, colored yellow and red here, that controls the entire lifecycle of the virus. It also encodes several proteins: the T-antigen (and a spliced version of it called the t-antigen) and three capsid proteins, VP1, VP2 and VP3. Only a few tiny segments, colored white here, are not used. Space is so limited in this genome that the capsid proteins are actually encoded with overlapping reading frames, such that the end portion of the gene for one protein also encodes for the beginning portion of the next protein. For more information on the parsimonious genome of SV40, take a look at the Protein of the Month feature at the European Bioinformatics Institute.

Steering the Life Cycle

SV40 infects primate cells, forcing its way inside and releasing its DNA circle. Once inside, it has two jobs: to replicate its DNA and to package it inside new viral capsids. Amazingly, SV40 only needs one protein, the T-antigen, to control both of these processes. Soon after the virus enters the cell, the cell's own synthetic machinery recognizes a TATA sequence at the center of the SV40 regulatory regions, shown in bright red here. The cell then creates a messenger RNA reading counterclockwise around the DNA circle. This mRNA is used to make the T-antigen protein (shown in more detail on the next page). Then the virus really gets to work. The T-antigen binds to the SV40 circle and helps to separate the strands, making way for the cell's polymerases to copy the DNA. It also directs the reading of the DNA in the opposite direction, clockwise around the strand, to create many copies of the capsid proteins.

SV40 and Cancer

In the normal lifecycle of the virus, SV40 enters cells, builds new viruses, and then kills the cell as the viruses are released. SV40 can also infect other mammals in a non-permissive mode. Then, the virus enters the cell but is unable to reproduce. However, T-antigen is formed and it can occasionally transform the cell into a cancer cell. The T-antigen binds to p53 and Rb, two proteins that are important in the control of growth. By blocking their normal function, the infected cell is allowed to multiply without control, leading to cancerous growth. Study of this rare event led to many of the early discoveries in the biology of cancer. More commonly, a similar mechanism allows papillomaviruses to infect cells and cause the unnatural growth of warts.

T-antigen protein. Flexible portions of the structure are shown schematically with dots.

The Amazing T-antigen

SV40 packs all of its functional needs into one remarkable, multifunctional protein. The T-antigen is composed of several functional parts, connected by flexible linkers. Structures of the three major pieces are available in the PDB. At one end, a helicase domain assembles with several other copies of the protein to form a six-fold ring (shown on the left from PDB entry 1n25 ). The hole is just big enough to encircle a DNA double helix. The central domain (PDB entry 1tbd ) has a small patch, shown here in green, that binds specifically to the regulatory region in the SV40 genome, anchoring the T-antigen complex in the proper place. The third domain interacts with cellular proteins, directing the various stages in the viral life cycle. It is shown here on the right bound to the Rb protein, shown in red (PDB entry 1gh6 ). In the cell, twelve copies of the protein assemble around the DNA to form a long tube, as shown at the bottom.

Exploring the Structure

You can look at the capsid of SV40 using PDB entry 1sva . The PDB file contains 6 chains, which are the ones that are experimentally unique in the crystal lattice. It is worth spending a little time with this file, to explore how the chains interweave and interlock to form the sturdy capsid. They are all identical in chemical structure, but they adopt slightly different structures to accommodate the unusual pseudosymmetry of this capsid. Then, go the file that contains the whole biological assembly (this can be found under Download/Display File, down at the bottom of the page), and look at the whole capsid. Be prepared to spend some time, though, because the whole structure has almost a million atoms! I have drawn only the backbone here, which greatly speeds up the graphics.

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The RCSB PDB Molecule of the Month by David S. Goodsell (The Scripps Research Institute and the RCSB PDB) presents short accounts on selected molecules from the Protein Data Bank. Each installment includes an introduction to the structure and function of the molecule, a discussion of the relevance of the molecule to human health and welfare, and suggestions for how visitors might view these structures and access further details. More

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